Protein imbalance from aneuploidy impairs mitochondria - Dataset 6: TMT-based global proteomics

ABSTRACT: Aberrant chromosomal content, or aneuploidy, profoundly affects cellular physiology. Even a gain of a single chromosome disrupts proteostasis due to overexpression of numerous proteins. Consequently, cells accumulate SQSTM1/p62-positive cytosolic bodies and show altered proteasomal and lysosomal activity. To elucidate the p62 interaction network in aneuploid cells, we conducted p62 immunoprecipitation and proximity labeling assays followed by mass spectrometry analysis. Our investigation revealed the enrichment of mitochondrial proteins within the cytosolic p62 interactome and proximome in aneuploid cells, but not in the proximome spatially confined to autophagosomes. Immunofluorescence confirmed increased colocalization of p62 with novel interactors and with mitochondrial proteins in polysomic cells. Moreover, we observed mitochondrial damage characterized by increased perinuclear clustering, reduced oxygen consumption, and reduced mitochondrial DNA abundance in polysomic cells. Furthermore, we demonstrate that polysomic cells exhibit reduced import of mitochondrial proteins and accumulation of mitochondria precursor proteins in the cytosol. Our data suggest that proteotoxic stress induced by chromosome gains leads to the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Markus Räschle  

LAB HEAD: Markus Räschle

PROVIDER: PXD052637 | Pride | 2025-05-12

REPOSITORIES: Pride